A low level of response (LR) to alcohol is an important endophenotype associated with an increased risk for alcoholism. However, little is known about how neural functioning may differ between individuals with low and high LRs to alcohol. This study examined whether LR group effects on neural activity varied as a function of acute alcohol consumption.
30 matched high- and low-LR pairs (N=60 healthy young adults) were recruited from the University of California, San Diego and administered a structured diagnostic interview and laboratory alcohol challenge followed by two fMRI sessions under placebo and alcohol conditions, in randomized order. Task performance and BOLD response contrast to high relative to low working memory load in an event-related visual working memory (VWM) task was examined across 120 fMRI sessions.
Both LR groups performed similarly on the VWM task across conditions. A significant LR group by condition interaction effect was observed in inferior frontal and cingulate regions, such that alcohol attenuated the LR group differences found under placebo (p<.05). The LR group by condition effect remained even after controlling for cerebral blood flow, age, and typical drinking quantity.
Alcohol had differential effects on brain activation for low and high LR individuals within frontal and cingulate regions. These findings represent an additional step in the search for physiological correlates of a low LR, and identify brain regions that may be associated with the low LR response.
Level of response; fMRI; visual working memory; cerebral blood flow
Excessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between DSM-IV alcohol dependence and all common copy number variations (CNV) with good reliability in the Study of Addiction: Genetics and Environment (SAGE).
All participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), as a part of three contributing studies. 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVpartition, PennCNV and QuantiSNP and only CNVs identified by all three software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory.
CNVs in 6q14.1 (P= 1.04 × 10−6) and 5q13.2 (P= 3.37 × 10−4) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2 there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation, and language delay. The CNV in 5q13.2 was validated whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution.
This is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence.
Copy Number Variations; Alcohol dependence; CNV Accuracy
Event-related oscillations (EROs) represent highly heritable neuroelectric correlates of cognitive processes that manifest deficits in alcoholics and in offspring at high risk to develop alcoholism. Theta ERO to targets in the visual oddball task has been shown to be an endophenotype for alcoholism. A family-based genome-wide association study was performed for the frontal theta ERO phenotype using 634583 autosomal single nucleotide polymorphisms (SNPs) genotyped in 1560 family members from 117 families densely affected by alcohol use disorders, recruited in the Collaborative Study on the Genetics of Alcoholism. Genome-wide significant association was found with several SNPs on chromosome 21 in KCNJ6 (a potassium inward rectifier channel; KIR3.2/GIRK2), with the most significant SNP at P = 4.7 × 10-10). The same SNPs were also associated with EROs from central and parietal electrodes, but with less significance, suggesting that the association is frontally focused. One imputed synonymous SNP in exon 4, highly correlated with our top three SNPs, was significantly associated with the frontal theta ERO phenotype. These results suggest KCNJ6 or its product GIRK2 account for some of the variations in frontal theta band oscillations. GIRK2 receptor activation contributes to slow inhibitory postsynaptic potentials that modulate neuronal excitability, and therefore influence neuronal networks.
Both linkage and association studies have been successfully applied to identify disease susceptibility genes with genetic markers such as microsatellites and Single Nucleotide Polymorphisms (SNPs). As one of the traditional family-based studies, the Transmission/Disequilibrium Test (TDT) measures the over-transmission of an allele in a trio from its heterozygous parents to the affected offspring and can be potentially useful to identify genetic determinants for complex disorders. However, there is reduced information when complete trio information is unavailable. In this study, we developed a novel approach to “infer” the transmission of SNPs by combining both the linkage and association data, which uses microsatellite markers from families informative for linkage together with SNP markers from the offspring who are genotyped for both linkage and a Genome-Wide Association Study (GWAS). We generalized the traditional TDT to process these inferred dosage probabilities, which we name as the dosage-TDT (dTDT). For evaluation purpose, we developed a simulation procedure to assess its operating characteristics. We applied the dTDT to the simulated data and documented the power of the dTDT under a number of different realistic scenarios. Finally, we applied our methods to a family study of alcohol dependence (COGA) and performed individual genotyping on complete families for the top signals. One SNP (rs4903712 on chromosome 14) remained significant after correcting for multiple testing Methods developed in this study can be adapted to other platforms and will have widespread applicability in genomic research when case-control GWAS data are collected in families with existing linkage data.
While there is extensive literature on the relationship between the P3 component of event-related potentials (ERPs) and risk for alcoholism, there are few published studies regarding other potentially important ERP components. One important candidate is the N4(00) component in the context of semantic processing, as abnormalities in this component have been reported for adult alcoholics.
A semantic priming task was administered to non-alcohol dependent male offspring (18 to 25 years) of alcoholic fathers [high risk (HR) n=23] and non-alcoholic fathers [low risk (LR) n=28], to study whether the two groups differ in terms of the N4 component. Subjects were presented with 150 words and 150 non-words. Among the words, 50 words (primed) were preceded by their antonyms (prime, n=50), whereas the remaining 50 words were unprimed. For the analysis, N4 amplitude and latency, as well as behavioral measures for the primed and unprimed words were considered.
A significant interaction effect was observed between semantic condition and group, where HR subjects did not show N4 attenuation for primed stimuli.
The lack of N4 attenuation to primed stimuli and/or inability to differentiate between primed and unprimed stimuli, without latency and reaction time being affected, suggest deficits in semantic priming, especially in semantic expectancy and/or post-lexical semantic processing in HR male offspring. Further, it indicates that it might be an electrophysiological endophenotype that reflects genetic vulnerability to develop alcoholism.
Semantic priming; N4; alcoholism; high risk; endophenotype
Twin studies provide strong evidence that there is a shared genetic liability that predisposes to a number of different psychiatric outcomes related to behavioral disinhibition. Further, alcohol dependence comorbid with other disinhibitory disorders is particularly heritable. Chromosome 2p14–2q14.3 has been linked to multiple psychiatric conditions related to behavioral undercontrol. In the Collaborative Study on the Genetics of Alcoholism (COGA), we previously reported linkage to this region with alcohol dependence (AD), suicide attempts (SUI), and conduct disorder (CD). In this study, we follow-up on these previous reports of linkage by combining the phenotypes in analyses that jointly consider the presence of multiple conditions. Linkage analyses of the combined phenotype of AD with CD or SUI results in a maximum LOD score of 5.4 in this region. In addition to this primary linkage peak, independent samples have reported linkage to other alcohol-related phenotypes across chromosome 2. Accordingly, we followed-up these linkage signals by testing for association with SNPs across chromosome 2 in a case–control sample, in which a subset of the cases consisted of alcohol-dependent probands from the linkage sample. We find evidence of association with the combined AD with CD or SUI phenotype, with 23 genes surviving permutation testing. The number of associated genes across the chromosome may explain the persistent linkage findings reported on chromosome 2 across a number of independent studies of alcohol and disinhibitory phenotypes. Further, none of the genes were located directly under the primary COGA linkage peak, which has implications for association tests following-up linkage peaks.
alcoholism; genetics; linkage; association; behavioral disinhibition
Depression and alcohol dependence are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35–60%. In addition, evidence from twin studies suggests that alcohol dependence and depression are genetically correlated. Here we report results from a genome-wide association study (GWAS) of a comorbid phenotype in which cases meet the DSM-IV symptom threshold for major depressive symptomatology and DSM-IV criteria for alcohol dependence.
Samples (N=467 cases and N=407 controls) were of European-American descent, and were genotyped using the Illumina Human 1M BeadChip array.
Although no SNP meets genome-wide significance criteria, we identify ten markers with p-values < 1 × 10−5, seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding p<1 × 10−3 are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, alcohol dependence, or other addiction-related phenotypes – such as CDH13, CSMD2, GRID1, and HTR1B – were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an alcohol dependence-only phenotype is modest.
These results underscore the complex genomic influences on psychiatric phenotypes, and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect alcohol dependence alone.
genetics of alcoholism; comorbidity; genetic risk; depressive syndrome
A low level of response (i.e., a low LR) to alcohol is a genetically influenced phenotype that predicts later alcoholism. While the low LR reflects, at least in part, a low brain response to alcohol, the physiological underpinnings of the low LR have only recently been addressed.
Forty-nine drinking but not yet alcoholic matched pairs of 18-25-year-old subjects (N = 98; 53% female) with low and high LRs as established in separate alcohol challenges were evaluated in two event-related functional magnetic resonance imaging (fMRI) sessions (placebo and ~ 0.7 ml/kg of alcohol) while performing a validated stop signal task. The high and low LR groups had identical blood alcohol levels during the alcohol session.
Significant high versus low LR group and LR group × condition effects were observed in blood oxygen level dependent (BOLD) signal during error and inhibitory processing, despite similar LR-group performance on the task. In most clusters with significant (corrected p<.05, clusters >1344 μl) LR group × alcohol/placebo condition interactions, the low LR group demonstrated relatively less, whereas the high LR group demonstrated more, error and inhibition-related activation after alcohol compared to placebo.
This is one of the first fMRI studies to demonstrate significant differences between healthy groups with different risks for a future life threatening disorder. The results may suggest a brain mechanism that contributes to how a low LR might enhance the risk for future heavy drinking and alcohol dependence.
alcohol; reaction; risk; fMRI
A variety of species and experimental designs have been used to study genetic influences on alcohol dependence, ethanol response, and related traits. Integration of these heterogeneous data can be used to produce a ranked target gene list for additional investigation.
In this study, we performed a unique multi-species evidence-based data integration using three microarray experiments in mice or humans that generated an initial alcohol dependence (AD) related genes list, human linkage and association results, and gene sets implicated in C. elegans and Drosophila. We then used permutation and false discovery rate (FDR) analyses on the genome-wide association studies (GWAS) dataset from the Collaborative Study on the Genetics of Alcoholism (COGA) to evaluate the ranking results and weighting matrices. We found one weighting score matrix could increase FDR based q-values for a list of 47 genes with a score greater than 2. Our follow up functional enrichment tests revealed these genes were primarily involved in brain responses to ethanol and neural adaptations occurring with alcoholism.
These results, along with our experimental validation of specific genes in mice, C. elegans and Drosophila, suggest that a cross-species evidence-based approach is useful to identify candidate genes contributing to alcoholism.
Many states require screening of individuals arrested for driving under the influence of alcohol (DUI) to determine recidivism risk and the need for treatment based on severity of alcohol problems. Several screening instruments use DSM-IV criteria for alcohol abuse and dependence to assess alcohol problems in this population, but whether they adequately measure alcohol problems in individuals with DUIs has not been examined. In addition, gender differences in DUI samples suggest that female offenders have more severe alcohol problems than male offenders. The current study examines differences in alcohol criteria functioning by DUI history and gender using an item response theory (IRT) approach.
Data from diagnostic interviews with 8605 participants in the Collaborative Study on the Genetics of Alcoholism, including 1655 who ever reported a DUI arrest (20% women), were used to examine differences in alcohol criteria functioning between men and women with and without DUIs. The factor underlying item response was conceptualized as unidimensional, representing alcohol problem severity.
Social/interpersonal problems, larger/longer, and inability/persistent desire to quit displayed greater discrimination of IRT-defined alcohol problem severity among individuals with DUIs than those without. Irrespective of DUI status, women had a higher threshold than men for time spent drinking or recovering. Women without DUIs had a higher threshold than similar men for social/interpersonal problems. Taken as a whole, the criteria yielded similar amounts of information in all groups.
DSM-IV criteria for alcohol abuse and dependence adequately detect alcohol problem severity in individuals with DUIs and some are better at detecting severity in this particularly high-risk group than in individuals without DUIs. However, the criteria as a whole are equally effective in measuring alcohol problem severity among individuals with and without DUIs, and may be used with confidence in screening DUI offenders.
DUI; Alcohol Use Disorder; Item Response Theory
The low level of response (LR) to alcohol is one of several genetically-influenced characteristics that increase the risk for heavy drinking and alcohol problems. Efforts to understand how LR operates through additional life influences have been carried out primarily in modest sized U.S.-based samples with limited statistical power, raising questions about generalizability and about the importance of components with smaller effects. This study evaluates a full LR-based model of risk in a large sample of adolescents from the U.K.
Cross-sectional structural equation models (SEM) were used for the approximate first half of the age 17 subjects assessed by the Avon Longitudinal Study of Parents and Children (ALSPAC), generating data on 1,905 adolescents (0 age 17.8 years, 44.2% males). LR was measured with the Self-Rating of the Effects of Alcohol (SRE) Questionnaire, outcomes were based on drinking quantities and problems, and standardized questionnaires were used to evaluate peer substance use, alcohol expectancies, and using alcohol to cope with stress.
In this young and large U.K. sample, a low LR related to more adverse alcohol outcomes both directly and through partial mediation by all three additional key variables (peer substance use, expectancies, and coping). The models were similar in males and females.
These results confirm key elements of the hypothesized LR-based model in a large U.K. sample, supporting some generalizability beyond U.S. groups. They also indicate that with enough statistical power multiple elements contribute to how LR relates to alcohol outcomes, and reinforce the applicability of the model to both genders.
ALSPAC; alcohol; level of response; structural equation models; adolescents
A coding variant in ADH1B (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by DSM-IV criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio of 0.34, 95% confidence interval 0.24, 0.48) for alcohol dependence, with genome-wide significance (6.6 × 10−10). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24 hour period (lifetime), with p = 3×10−13. We also tested the effects of this allele on the development of alcoholism in adolescents and young adults and demonstrated a significant protective effect. This variant has the strongest effect on risk for alcohol dependence of any tested in European populations.
alcohol dependence; ADH1B; alcohol dehydrogenase; protective allele; genetics; association study
Aims: Alcohol acutely reduces agitation and is widely used in social situations, but the neural substrates of emotion processing during its intoxication are not well understood. We examine whether alcohol's social stress dampening effect may be via reduced activity in the cortical systems that subserve awareness of bodily sensations, and are associated with affective distress. Methods: Blood oxygen level-dependent activation was measured through 24 functional magnetic resonance imaging sessions in 12 healthy volunteers during an emotional face-processing task following ingestion of a moderate dose of alcohol and a placebo beverage. Results: Results revealed that bilateral anterior insula response to emotional faces was significantly attenuated following consumption of alcohol, when compared with placebo (clusters >1472 μl; corrected P < 0.05). Conclusion: Attenuated response in the anterior insula after alcohol intake may explain some of the decreased interoceptive awareness described during intoxication.
Despite twin studies showing that 50–70% of variation in DSM-IV cannabis dependence is attributable to heritable influences, little is known of specific genotypes that influence vulnerability to cannabis dependence. We conducted a genomewide association study of DSM-IV cannabis dependence. Association analyses of 708 DSM-IV cannabis dependent cases with 2,346 cannabis exposed nondependent controls was conducted using logistic regression in PLINK. None of the 948,142 SNPs met genomewide significance (p < E−8). The lowest p-values were obtained for polymorphisms on chromosome 17 (rs1019238 and rs1431318, p-values at E−7) in the ANKFN1 gene. While replication is required, this study represents an important first step towards clarifying the biological underpinnings of cannabis dependence.
Although there are multiple indications that alcohol can alter many physiological brain functions, including cerebral blood flow (CBF), studies of the latter have generally used small or modest sized samples. Few investigations have yet evaluated how CBF changes after alcohol relate to subsets of subjects with elevated alcoholism risks, such as those with lower levels of response (LR) to alcohol. This study used arterial spin labeling (ASL) after alcohol administration to evaluate a large sample of healthy young men and women with low and high alcohol responses, and, thus, varying risks for alcohol use disorders (AUD).
Healthy young adult social drinkers with low and high LR (N=88, 50% female) matched on demography and drinking histories were imaged with whole brain resting ASL ~1 hour after ingesting ~3 drinks of ethanol and after a placebo beverage (i.e., 178 ASL sessions). The relationships of CBF changes from placebo to alcohol for subjects with low and high LR were evaluated.
CBF increased after alcohol as compared to placebo in five frontal brain regions. Despite identical BACs, these increases with alcohol were less prominent in individuals who required more drinks to experience alcohol-related effects (i.e., had a lower LR to alcohol). The LR group differences remained significant after covarying for recent drinking quantities.
The results confirm that alcohol intake is associated with acute increases in CBF, particularly in frontal regions. Less intense CBF changes were seen in subjects with a genetically influenced characteristic, a low LR to alcohol, that relates to the future risk of heavy drinking and alcohol problems.
alcohol; arterial spin labeling; level of response to alcohol; alcoholism risk
Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome-wide association study (GWAS) of an ERO endophenotype – frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty-two SNPs of the Illumina HumanHap 1M microarray were selected from the theta ERO GWAS for replication in family-based samples (N = 1,095), with four markers revealing nominally significant association. The most significant marker from the two-stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher’s combined P = 3.68 × 10−6). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P = 1.53 × 10−4), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM-IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case-controls (P = 0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case-control and family-based samples (P = 0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders.
serotonin receptor gene (HTR7); serotonin receptor (5-HT7); event-related oscillation (ERO); alcohol dependence; genome-wide association study (GWAS)
The recent proposal to dissolve the National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse and create a new institute for substance use, abuse, and addiction will require significant effort by the staff of both institutes, the Advisory Councils, and outside experts to overcome complex challenges that could threaten its success. Although integration of the grants portfolios can be achieved, harmonization of goals and policies related to legal use of alcohol versus illegal consumption of drugs will present serious challenges. Consolidating the infrastructure of the two existing institutes would entail avoiding encroachment on grant funding. A new institute for substance use, abuse, and addiction would require an enormous amount of cooperation from other institutes since the portfolios of research on alcohol, tobacco, and other drug abuse should logically be transferred to the new institute. In the near term, a structural reorganization would be less efficient and more costly than the individual institutes are currently. Increasing efficiency and reducing costs over time will necessitate careful strategic planning. Success in this difficult task would be made easier and less costly by first implementing carefully placed building blocks of increasing functional reorganization. The newly created institute should increase opportunities for specialization within disorders of addiction, attract new leadership, and build a novel strategic plan that will energize scientists and staff and incorporate ideas of stakeholders to advance the public good in preventing and treating alcohol, tobacco, and all addictions. Attention must be paid to the devil in the details.
Several genome-wide association and candidate gene studies have linked chromosome 15q24–q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking the CHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were recruited from families affected with alcoholism (either as a first or second degree relative) and the comparison families. Participants completed the SSAGA interview, a comprehensive assessment of alcohol and other substance use and related behaviors. Using the Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. Multivariate analysis using a Cox proportional hazards model further revealed that these variants significantly predict the age at onset of habitual smoking among daily smokers. These variants were not in high linkage disequilibrium (0.28
Patterns of drinking and alcohol problems change with age. However, few studies use multiple data points and detailed history spanning early adulthood to middle age. This study reports such data from 373 men in the San Diego Prospective Study.
Data were generated at baseline (T1) at ~age 20, and through face-to-face follow-up interviews ~every 5 years in >90% of these eligible Caucasian and relatively higher educated men. Subjects were placed into 4 groups regarding their course: 62.5% with no alcohol use disorder (AUD); 17.2% with AUD onset 5 years before the 25-year followup.
On a univariate level, low level of response (LR) to alcohol, family history of AUDs, and higher Novelty Seeking at ~age 20 predicted AUDs with onset before age 30 (mean age ~25), but among these only LR predicted later onset (mean age 38) as well. Additional predictors of AUDs included demography (lower education), and greater involvement with alcohol, drugs, and nicotine prior to T1. Sustained remission from AUDs among alcoholics was predicted by lower T1 and T10 drinking frequencies, and being separated or divorced at T10, along with a trend for higher Reward Dependence.
These data indicate that information available in the late teens to early 20’s can help predict the future onset and course of AUDs, and underscore the importance of longitudinal studies in substance use disorders.
alcohol; sensitivity; alcoholism clinical course
A low level of response to alcohol during an individual’s early experience with alcohol is associated with an increase risk for alcoholism. A family-based genome-wide linkage analysis using sibling pairs that underwent an alcohol challenge where the level of response to alcohol was measured with the Subjective High Assessment Scale (SHAS) implicated the 10q terminal region. CYP2E1, a gene known for its involvement with ethanol metabolism, maps to this region.
Variance component multipoint linkage analysis was performed on a combined map of single nucleotide polymorphism (SNP) and microsatellite data. To account for the heterogeneity evident in the dataset, a calculation assuming locus heterogeneity was made using the HLOD (heterogeneity LOD) score. Association between SNP marker allele counts and copy number and SHAS scores were evaluated using a logistic regression model.
Linkage analysis detected significant linkage to CYP2E1 which was diminished due to apparent locus heterogeneity traced to a single family with extreme phenotypes. In retrospect, circumstances recorded during testing for this family suggest that their phenotype data are likely to be unreliable. Significant allelic associations were detected for several CYP2E1 polymorphisms and the SHAS score. DNA sequencing from families that contributed the greatest evidence for linkage did not detect any changes directly affecting the primary amino acid sequence. With the removal of a single family, combined evidence from microsatellites and SNPs offer significant linkage between the level of response to alcohol and the region on the end of chromosome 10.
Combined linkage and association indicate that sequence changes in or near CYP2E1 affect the level of response to alcohol providing a predictor of risk for alcoholism. The absence of coding sequence changes indicates that regulatory sequences are responsible. Implicating CYP2E1 in the level of response to alcohol allows inferences to be made about how the brain perceives alcohol.
level of response to alcohol; linkage analysis; association analysis; combined linkage and association; CYP2E1; locus heterogeneity
Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders. There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders. Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 (CRHR1) in the environmental stress response and ethanol self-administration in animal models. The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis.
We analyzed a sample from the Collaborative Study on the Genetics of Alcoholism (COGA) comprising 1049 Caucasian subjects from 209 families (including 472 alcohol-dependent individuals). Quantitative transmission disequilibrium test (QTDT) and family-based association test (FBAT) were used to test the association, and false discovery rate (FDR) was applied to correct for multiple comparisons.
Significant associations (p < 0.05) were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene.
Our results suggest that CRHR1 may be involved in modulating the P3 component of the ERP during information processing and in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders.
P3; Disinhibition; Endophenotype; Stress; Corticotropin Releasing Factor (CRF)
Alcohol use disorders are influenced by many interacting genetic and environmental factors. Highlighting this complexity is the observation that large genome-wide association experiments have implicated many genes with weak statistical support. Experimental model systems, cell culture and animal, have identified many genes and pathways involved in ethanol response, but their applicability to the development of alcohol use disorders in humans is undetermined. To overcome the limitations of any single experimental system, the analytical strategy used here was to identify genes that exert common phenotypic effects across multiple experimental systems. Specifically, we (1) performed a mouse linkage analysis to identify quantitative trait loci that influence ethanol-induced ataxia; (2) performed a human genetic association analysis of the mouse-identified loci against ethanol-induced body sway, a phenotype that is not only comparable to the mouse ethanol-ataxia phenotype but is also a genetically influenced endophenotype of alcohol use disorders; (3) performed behavioral genetic experiments in Drosophila showing that fly homologs of GPC5, the member of the glypican gene family implicated by both the human and mouse genetic analyses, influence the fly’s response to ethanol; and (4) discovered data from the literature demonstrating that the genetically implicated gene’s expression is not only temporally and spatially consistent with involvement in ethanol-induced behaviors but is also modulated by ethanol. The convergence of these data provides strong support to the hypothesis that GPC5 is involved in cellular and organismal ethanol response and the etiology of alcohol use disorders in humans.
alcoholism; response to alcohol; glypican; behavior
This study’s aims were to map loci linked to self-rating of the effects of alcohol and to determine if there was overlap with loci previously mapped for other substance dependence phenotypes in an American Indian community at high risk for substance dependence.
Each participant gave a blood sample and completed a structured diagnostic interview using the Semi Structured Assessment for the Genetics of Alcoholism (SSAGA). Retrospective report of responses to alcohol during the FIRST FIVE TIMES they had ever drank alcohol was estimated from the Self-Rating of the Effects of Alcohol (SRE) questionnaire for each participant. Genotypes were determined for a panel of 791 micro-satellite polymorphisms in 381 members of multiplex families using SOLAR.
Analyses of multipoint variance component LOD scores, for the FIRST FIVE TIMES phenotype, revealed two loci that had a LOD score greater than 3.0 on chromosomes 6 and 9. Additionally, 3 locations were identified with LOD scores above 2.0 on chromosomes 10, 12, 17.
These results corroborate the importance of regions on chromosome 6 and 9 highlighted in prior segregation studies in this and other populations for substance dependence-related phenotypes, as well as an area on chromosome 10 previously identified for the FIRST FIVE TIMES phenotype in the collaborative study on the genetics of alcoholism. These studies additionally lend further support the construct that the SRE may represent an important endophenotype associated with alcohol and other substance dependence.
American Indians; alcohol dependence; linkage studies; SRE
Sensation seeking is a heritable personality trait that has been reliably linked to behavior disorders. The dopamine system has been hypothesized to contribute to individual differences in sensation seeking, and both experimental and observational studies in humans and non-human animals provide evidence for this relationship. We present here a candidate-system approach to genetic association analysis of sensation seeking, in which single nucleotide polymorphisms (SNPs) from a number of dopaminergic genes were analyzed. Using 273 SNPs from eight dopamine genes in a sample of 635 unrelated individuals, we examined the aggregate effects of those SNPs significantly associated with sensation seeking. Multiple SNPs in four dopamine genes accounted for significant variance in sensation seeking. These results suggest that aggregation of multiple SNPs within genes relevant to a specific neurobiological system into a “genetic risk score” may explain a nontrivial proportion of variance in human traits.
sensation seeking; dopamine; candidate gene; association study
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